CN106267160A - 一种用于治疗外周神经损伤的神经营养因子类缓释团聚体及其应用 - Google Patents
一种用于治疗外周神经损伤的神经营养因子类缓释团聚体及其应用 Download PDFInfo
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Abstract
本发明涉及一种治疗外周神经损伤的神经营养因子类缓释团聚体及其制备与应用。神经营养因子类缓释团聚体包含聚乙烯精氨酸天冬氨酸甘油醛(PEAD)、粘多糖(GAGs)和神经营养因子(NTFs)，通过改变各组分间的不同配比及NTFs种类，提高该缓释团聚体的各项性能。本发明的神经营养因子类缓释团聚体制备工艺简单，载药量大，稳定性好，体内易降解，安全无副作用，长效缓释作用显著，满足理想的修复外周神经损伤生物材料的要求。
Description
技术领域
本发明涉及一种用于治疗外周神经损伤的神经营养因子类缓释团聚体及其应用，特别涉及装载碱性成细胞生长因子与神经生长因子的缓释团聚体及其应用。
背景技术
退行性疾病是一种严重的疾病，并且可致残疾，而引起外周神经损伤的原因主要来自于车祸事故、肿瘤、先天性畸形、压缩或挫伤。神经损伤表现为部分或全部的运动神经和感觉神经以及自主神经功能的丧失，其难愈的原因之一为生长因子的合成与分泌减少。修复神经损伤的方法有很多种，常见的有自体移植修复技术和基因工程管道技术。在临床上，自体神经移植技术被广泛应用于外周神经缺陷的桥接。但它受制于宿主的免疫排斥从而使神经功能不能完全的恢复。自体移植修复技术的不足促使科学家们为治疗外周神经疾病寻找新的方法。
神经病理性疼痛是神经损伤后最常见的表现症状，其疼痛的难忍性严重影响患者的生活质量。病因主要为受损神经细胞的胞膜上Na+离子通道和电压门控Ca2+离子通道开放增加，形成离子流并释放疼痛物质(如P物质，乙酰胆碱)，导致神经的兴奋性增高并引起感觉功能的异常。但将治疗疼痛性药物加入神经修复材料中，虽可缓解疼痛的发展，但同时抑制轴突的再生，不利于外周神经的修复。
神经营养因子是一类由神经所支配的组织和胶质细胞分泌和产生并促进神经元生长与存活的蛋白类物质。包括碱性成纤维生长因子(bFGF)、神经生长因子(NGF)、脑源性生长因子(BDNF),神经营养因-3,4,5(NT-3，-4，-5),神经胶质细胞神经因子(GDNF)，胶质生长因子(GCF)，酸性成纤维生长因子(aFGF)等。它们具有促进神经周围血管的生成和营养神经的双重作用并广泛用于神经损伤的治疗。
近年来,生物工程材料的飞速发展为外周神经损伤的治疗带来福音。常见的用于治疗外周神经损伤的高分子生物材料包括：聚乙醇酸、聚乳酸、聚羟基丁酸盐、硅胶、聚四氟乙烯、聚吡咯、壳聚糖等。虽然此类材料制成的神经导管对实验性锯齿类动物外周神经损伤的治疗存在一定的治疗效果，但其存在的不可降解性或组织不相容性，限制其临床应用。
另外，临床上对于由牵拉导致神经断裂的修复主要依靠直接缝合术来实现，但是对于缺损较长的神经，此法不适用。另外，运用生物膜包裹雪旺细胞组成的细胞型生物蛋白胶复合体，能够促进轴突的再生，可修复10mm的神经缺损伤；但是由于操作的复杂性及结果的不稳定性，甚至产生的免疫排斥，导致其临床应用受限。此外，以胶原为基质的导管或支架，容易引起排异反应，并且无法发挥神经信号传导功能。已有的高分子聚合材料无法同时满足良好的组织相容性和生物有效性。
近年来，不少国家的科研机构和企业投入了大量的人力、物力与财力对神经修复材料进行探索。但是对于寻找或合成一种理想的神经修复材料：即具有良好的力学性能和空间结构，为神经再生提供最佳的理化和生物学微环境，且能实现神经吻合操作的快捷、简便、安全和预后好的多重目的,仍存在一定的差距。因此，制备一种理想的神经缺损区的修复材料势在必行。
发明内容
本发明的目的在于克服现有药物或技术的缺陷，提供一种新型治疗外周神经损伤的神经营养因子类缓释团聚体，该缓释团聚体具有良好的促进损伤神经轴突的再生且制备简单，安全无副作用，仅需一次注射便可达到长期的治疗效果，保证手术操作简便快捷的完成。
本发明人通过大量的动物试验和资料查阅发现，外周神经损伤治愈的效果不理想，其主要难题之一是现阶段没有一种生物材料可同时保证外周神经修复所需的所有最佳条件。发明人通过大量的试验，发明出一种新型治疗外周神经损伤的神经营养因子类缓释团聚体，可满足理想的神经再生和修复的需要。
本发明的一种治疗外周神经损伤的神经营养因子类缓释团聚体，其原料组成包含聚乙烯精氨酸天冬氨酸甘油醛、粘多糖和神经营养因子，通过改变各组分间的不同配比或神经营养因子种类，缓控药物的释放并保证其在组织内的可控降解。
聚乙烯精氨酸天冬氨酸甘油醛(PEAD)是由天冬氨酸和精氨酸以及甘油二酯为原料经缩合反应制备的一种聚合阳离子。试验表明，PEAD具有良好的组织相容性，安全无毒副作用，可生物降解，适合作为人工神经修复材料用于外周神经损伤的治疗。
上述的神经营养因子类缓释团聚体，其各组分的质量比为：聚乙烯精氨酸天冬氨酸甘油醛4～8，粘多糖0.5～3，神经营养因子0.0001～0.2。进一步优选地，其各组分的质量比为聚乙烯精氨酸天冬氨酸甘油醛5，粘多糖1～3，神经营养因子0.001～0.1。
上述的神经营养因子类包含包含碱性成纤维生长因子(bFGF)、神经生长因子(NGF)、脑源性生长因子(BDNF),神经营养因-3,4,5(NT-3，-4，-5)、血管内皮生长因子(VEGF)、神经胶质细胞神经因子(GDNF)、血小板衍生因子(PDGF)、酸性成纤维生长因子(aFGF)的一种或几种组合。
上述的神经营养因子类缓释团聚体通过进一步加入各类药用辅料的一种或几种组合，可进一步制成的剂型包括冻干粉、胶浆、软膏或输液剂。
上述的药用辅料包括硬脂酸类物质和羧甲基纤维素类物质或它们的混合物。
本发明还提供了一种制备上述的神经营养因子类缓释团聚体的制备方法，该方法包括以下步骤：
①取粘多糖，用生理盐水溶解，配制成1～20mg/mL的溶液；
②取聚乙烯精氨酸天冬氨酸甘油醛，用生理盐水溶解，配制成1～20mg/mL的溶液；
③将神经营养因子加入步骤①配制的粘多糖溶液中，20～35℃的条件下静置25-40分钟；
④将步骤②配制的聚乙烯精氨酸天冬氨酸甘油醛溶液加入步骤③得到的溶液中，在20～35℃的条件下搅拌3～12小时。
上述的神经营养因子类缓释团聚体主要应用于治疗外周神经损伤，包括挤压伤，横断伤和缺损伤，此外还可用于创面愈合、心肌缺血的辅助治疗。
与现有技术相比，本发明制备的神经营养因子类缓释团聚体的优点在于其内部特殊的空间结构，能发挥各种修复材料的优势并弥补其不足，满足理想的修复外周神经损伤生物材料的要求，其特点主要体现在：①带正电荷的PEAD和神经营养因子与带负电荷的粘多糖通过静电离子的相互作用将三者结合，从而使神经营养因子紧密结合粘多糖的同时又与PEAD存在一定的斥力，保证团聚体连续缓释神经营养因子的目的；②装载神经营养因子的种类丰富，质量较大并可实现多种类型神经营养因子的不同组合；③作为该缓释微球组份之一的PEAD，其合成所需的条件、设备及制备过程均简易，原料来源广泛廉价；④该缓释团聚体稳定性好，包封率高，粒径均匀，安全无副作用且具有较好的组织相容性和生物活性，对外周神经损伤的治疗效果显著。
附图说明
图1为本发明神经营养因子类缓释团聚体的结构(a:PEAD、粘多糖、神经营养因子三者结合的模式图；b:缓释团聚体的扫面电镜图)；
图2为本发明神经营养因子类缓释团聚体同时装载碱性成细胞生长因子和神经生长因子在不同时间点所绘制的释放曲线；
图3为本发明神经营养因子类缓释团聚体装载碱性成细胞生长因子治疗外周神经损伤时测试的脚步印迹(a:各组在第四周拍摄的脚印；b:各组大鼠在每周统计的SFI)；
图4为本发明神经营养因子类缓释团聚体装载碱性成细胞生长因子治疗外周神经损伤时拍摄的透射电镜图(a:各组大鼠坐骨神经拍摄的投射电镜图；b.各组大鼠髓鞘厚度的统计；c.各组大鼠轴突直径统计的结果)。
具体实施方式
下面通过具体实施方式对本发明作进一步详细说明。但本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。另外，实施例中未注明具体技术操作步骤或条件者，均按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1.外周神经损伤动物模型的建立
a.大鼠坐骨神经挤压伤模型
选用SPF级Wistar大鼠，在学校实验动物中心分笼饲养，保持室温22℃，自然光照，自由摄食。将大鼠依次用10％水合氯醛腹腔注射麻醉，在其右腿坐骨神经切记处切开，用玻璃分针分离坐骨神经，距梨状肌下缘远侧约1.5cm用静脉夹夹持2min,造成中度挫伤，采用无创细线(5/0)缝合肌肉和皮肤并用碘伏消毒。假手术组只需要切开缝合即可。整个手术过程中温度维持在37℃以防止低温导致造模Wistar大鼠死亡。
b.大鼠坐骨神经横断伤模型
选用SPF级Wistar大鼠，在学校实验动物中心分笼饲养，保持室温22℃，自然光照，自由摄食。将大鼠依次用10％水合氯醛腹腔注射麻醉，在其右腿坐骨神经切记处切开，玻璃分针分离坐骨神经并运用手术刀片在距神经分叉的1.5cm处将其切断，在体式显微镜下对合断端并运用10-0无创缝合线进行端端缝合，肌肉复位，缝合切口用碘伏消毒。假手术组只需要暴露坐骨神经并缝合肌肉和皮肤即可。整个手术过程中温度维持在37℃以防止低温导致造模的Wistar大鼠死亡。
实施例2.神经营养因子类缓释团聚体的制备
a.PEAD的合成：
首先将称量的乙二醇二环氧甘油醚(EGDE)1000mg，叔丁氧羰基(t-BOC)保护的天冬氨酸(ASP)1340mg和叔基溴化铵(TBAB)50mg放入10mL的微波反应瓶并在其加入0.6mL的二甲基甲酰胺(DMF)充分混匀后，于120℃的微波反应器加热20min，获得一种粘稠的橙色液体；然后分别加入5mL的三氟乙酸(TFA)和20mL的二氯甲烷(DCM)室温搅拌2h萃取中间体聚乙烯-天冬氨酸甘油酯(PED)；随后将770mg的ASP，323mg的N-hydrosuccinimide(NHS)，753mg的二环己基碳二亚胺(DCC)加入至35mL的DMF溶液并在手套箱中搅拌2h得到一种有沉淀的乳橙色液体，将此液体吸入至50mL的离心管并在12000rpm/min的高速离心机离心10min，吸取上清，减压蒸发得到分子量为73,750Da的PEAD，并在1H核磁共振波谱中观察到1.7和1.9ppm对应精氨酸基团的质子并在4.1ppm为天冬氨酸的氢。
b.不同配比的神经营养因子类缓释团聚体的制备
按照表1各组分投料配比不同制备的神经营养因子类缓释团聚体，具体操作为：
①粘多糖溶液的配制：取粘多糖，用生理盐水溶解，配制成10mg/mL的溶液；
②PEAD溶液的配制：取PEAD，用生理盐水溶解，配制成10mg/mL的溶液；
③神经营养因子溶液的配制：取神经营养因子，用生理盐水溶解，配制成10mg/mL的溶液；
④在反应器皿将步骤③配制的神经营养因子溶液加入步骤①配制的粘多糖溶液，充分搅拌均匀后，30～35℃的条件下静置30分钟；
⑤将步骤②配制的PEAD溶液加入步骤④配制的溶液，在30～35℃的条件下搅拌6小时；同时可添加药用辅料的一种或多种混合，制备冻干粉、胶浆、软膏或输液剂。其中，图1为实验组2C制备的神经生长因子缓释团聚体的结构(a:PEAD、粘多糖、神经生长因子三者结合的模式图；b:缓释团聚体的扫面电镜图)；图2为实验组3C制备的神经营养因子类缓释团聚体同时装载碱性成细胞生长因子和神经生长因子时，在不同时间点所绘制的释放曲线；图3为实验组1C制备的碱性成细胞生长因子缓释团聚体与对照组3、4、5在治疗大鼠坐骨神经挤压伤模型所测试的脚步印迹，由3a的结果可知，对照组5(Model)和对照组3(Vehicle)在治疗的第28天，爬行的脚印模糊，轮廓不清，而对照组4(Free bFGF)大鼠爬行的脚印轮廓较清晰，各脚趾伸展较开，但不及实验组1C(bFGF-Coacervate)，由各组脚印统计SFI(神经功能指数)的分析结果，实验组1C随治疗天数的推移，其SFI值不断变大，说明大鼠运动功能的恢复不断改善，由此，实验组1C对外周神经损伤大鼠的运动功能的恢复效果最佳；图4为实验组1C制备的碱性成细胞生长因子缓释团聚体与对照组3、4、5在治疗大鼠坐骨神经挤压伤所模型拍摄的透射电镜图，由4a的电镜结果，对照组5和对照组3神经数目稀疏，排列紊乱，髓鞘厚度较薄并出现不同程度的肿胀，而对照组4这样的现象有所改善，实验组1C神经内部结构改善的最明显，接近正常，图4b和图4c分别对各组大鼠髓鞘的厚度和轴突的直径进行统计，由统计的结果，对照组4与对照组3、5在髓鞘的厚度和轴突的直径存在统计学差异(P＜0.001)，而实验组1C与对照组4也存在一定的统计学意义(P＜0.01)，说明实验组1C对增加坐骨神经损伤大鼠的髓鞘厚度和轴突直径，效果最佳，由此，装载10μg碱性成细胞生长因子缓释团聚体对改善损伤神经内部的病理结构，效果最佳。
表1各组神经营养因子类缓释微球的组成
注：“-”代表此项不添加物质。
实施例3.动物给药与疗效评价
将坐骨神经挤压伤或横断伤模型的Wistar大鼠在缝合肌肉和皮肤后，将表1中各实验组和对照组制备的神经营养因子类缓释团聚体通过30G针头及时递送入损伤的坐骨神经区域。
神经修复的效果评价指标如下：
a.行为学：分别运用脚步印迹及热板试验对坐骨神经损伤后的Wistar大鼠进行运动功能和感觉功能恢复测试，时间为给药后的第1、2、3、4周；
b.组织形态学：给药治疗1个月后，处死各组大鼠，收集损伤的坐骨神经，制作病理切片并进行HE染色，Massion染色及透射电镜；
c.结构和功能蛋白的表达水平：收集损伤的坐骨神经，运用Western Blot法检测各组损伤神经内GAP-43、MAP-2、MBP、S-100β及NF-200的表达水平。
表2：实验组与对照组疗效评价
各试验组从行为学、组织形态学、结构和功能蛋白水平三方面进行综合评分，对照未经任何处理的神经损伤同时期的情况，将各指标分级，“-”表示无效，“+”表示三项指标均有改善或升高，其中，行为学中的“+”表示运动和感觉持续改善，组织形态学中的“+”表示再生神经纤维数目增多，排列规整，轴突再生和再髓鞘化情况有所改善，结构和功能蛋白水平中的“+”表示此类蛋白的表达升高，“+”越多表示各指标改善越明显或表达越高，即神经功能恢复的速度和效果越佳。
从上述实验结果可知，本发明的神经营养因子类缓释团聚体能显著提高损伤后坐骨神经的运动和感觉的恢复，具有良好的促进损伤区轴突和髓鞘的再生，并大量合成和分泌相应的结构和功能蛋白，使其完整的外周神经结构快速生成，明显好于已有报道的修复材料和非本发明的材料组合，差异结果具有显著性。另外，外周神经损伤恢复的效果与本发明中神经营养因子种类的选择，组合及其含量有密切联系。
上述详细说明是针对发明的可行实施例的具体说明，该实施例并非用以限制本发明的专利范围，凡未脱离本发明的等效实施或变更，均应当包含于本发明的专利范围内。
另外，本领域技术人员还可在本发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然，这些依据本发明精神所做的各种修改、添加和替换等变化，都应包含在本发明所要求保护的范围之内。
Claims (10)
1.一种用于治疗外周神经损伤的神经营养因子类缓释团聚体,其特征在于：该神经营养因子类缓释团聚体由聚乙烯精氨酸天冬氨酸甘油醛、粘多糖和神经营养因子组成。
2.根据权利要求1所述用于治疗外周神经损伤的神经营养因子类缓释团聚体，其特征在于：其各组分的质量比为聚乙烯精氨酸天冬氨酸甘油醛4～8，粘多糖1～3，神经营养因子0.0001～0.2。
3.根据权利要求2所述用于治疗外周神经损伤的神经营养因子类缓释团聚体，其特征在于：其各组分的质量比为聚乙烯精氨酸天冬氨酸甘油醛5，粘多糖1～3，神经营养因子0.001～0.1。
4.根据权利要求1所述用于治疗外周神经损伤的神经营养因子类缓释团聚体，其特征在于：所述的神经营养因子选自碱性成纤维生长因子、神经生长因子、脑源性生长因子、神经营养因-3,4,5、血管内皮生长因子、神经胶质细胞神经因子、血小板衍生因子、酸性成纤维生长因子的一种或几种组合。
5.一种含有权利要求1所述神经营养因子类缓释团聚体的药物制剂，其特征在于：该药物制剂为冻干粉、胶浆、软膏或输液剂，由所述神经营养因子类缓释团聚体和药用辅料制得。
6.根据权利要求5所述的药物制剂，其特征在于：所述的药用辅料为硬脂酸类物质、羧甲基纤维素类物质或它们的混合物。
7.一种根据权利要求1-4任一项所述用于治疗外周神经损伤的神经营养因子类缓释团聚体的制备方法，其特征在于该方法包括如下步骤：
①取粘多糖，用生理盐水溶解，配制成1～20mg/mL的溶液；
②取聚乙烯精氨酸天冬氨酸甘油醛，用生理盐水溶解，配制成1～20mg/mL的溶液；
③将神经营养因子加入步骤①配制的粘多糖溶液中，20～35℃的条件下静置25-40分钟；
④将步骤②配制的聚乙烯精氨酸天冬氨酸甘油醛溶液加入步骤③得到的溶液中，在20～35℃的条件下搅拌3～12小时。
8.根据权利要求7所述用于治疗外周神经损伤的神经营养因子类缓释团聚体的制备方法，其特征在于：步骤①中粘多糖溶液的配制浓度为5-10mg/mL；步骤②中聚乙烯精氨酸天冬氨酸甘油醛溶液的配制浓度为5-10mg/mL。
9.权利要求1-4任一项所述的神经营养因子类缓释团聚体在制备治疗外周神经损伤、创面或心肌缺血的药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述的外周神经损伤包括外周神经的挤压伤、横断伤和缺损伤。
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